| 1. |
- Holmbom, Martin, 1984-
(författare)
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Clinical Impact of Bloodstream Infections – Characterization, Risk factors and Outcome
- 2021
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Bloodstream infection (blood poisoning) and antibiotic resistance are increasing worldwide, and already cause the loss of millions of human lives each year. According to the World Health Organisation (WHO), bloodstream infections (BSIs) represent 20% of global mortality on a par with cardiac infarct, stroke, and major trauma. BSI may occur when bacteria from a focus of infection gain access to the circulation (bacteraemia). BSIs are usually divided into two subclasses: community- and hospital-onset infections, since disease this involves different patient groups, types of bacteria, and reasons for infection. Compared to other countries, Sweden has been fortunate in having a relatively low death rate from BSI and low antibiotic resistance. However, as our lifestyle changes, the age of the population increases with more disease as a result, and as the healthcare system responds, death from infection and antibiotic resistance are on the increase. It is important that we recognise ”warning symptoms” if we are to manage BSIs correctly and initiate effective treatment. It is difficult to design individualised empirical treatment, so it is very important to be aware of risk factors for BSI and local resistance patterns, and to have an effective management programme. Bacterial resistance to antibiotics is an increasing problem, especially in bowel organisms that can cause infections that are very difficult to treat. In short, antibiotic resistance arises as a result of evolutionary processes where bacteria protect themselves by developing resistance genes. These genes can be exchanged between similar organisms or transmitted to others that in turn cause resistant infection. The use of antibiotics leads to an evolutionary/selection process leading to resistance in bacteria, both normal and pathogenic, enabling resistant organisms to survive, thrive, and go on to cause infection. Antibiotic resistance is a threat to global health. This thesis aims to increase our awareness of a large group of patients who suffer bloodstream infection. BSIs are increasing globally, and the death toll is high. Antibiotic resistance is an increasing threat to the health of the population, and we are inundated by alarming reports of resistance getting out of control. What is the situation in Sweden, and can we identify risk factors for BSI and mortality? In Study I, our aim was to study the incidence and mortality of BSI in Östergötland. To be able to do this, a large patient population stretching over several years was required. The study design was thus population-based in the form of an observational cohort study where all blood culture results from 2000 to 2013 were analysed, and evaluated from clinical data. A total of 109,938 results were analysed resulting in 11,480 BSIs. We saw that the incidence of BSI increased by 64% (mostly community-onset BSIs). We also saw that mortality increased by 45%. These results illustrate the importance of nationwide cooperation to combat the increasing problem of BSI and its mortality, and the establishment of a nationwide BSI register. The aim of Study II was to assess resistance development in Östergötland and its relationship to mortality. A total of 9,587 microorganisms were analysed between 2008 and 2016. We observed an increase in quinolone resistance (3.7-7.7%) and cephalosporin resistance (2.5-5.2%) amongst Enterobacteriaceae. We then looked at BSIs caused by multiresistant bacteria showing a total of 245 cases (2.6%); an increase of 300%. Despite this, we did not see an increased mortality in this group. There are several possible explanations for the increase in BSI mortality of which antibiotic resistance is a predominant factor globally. We were unable to show this in our study, even so mortality is increasing and is currently at a high level. In Study III we therefore analysed risk factors associated with death during a community-acquired BSI, focusing on preliminary prehospital and hospital management. In a retrospective case-control study on 195 deaths matched 1:1 regarding age, gender, and microorganism, with 195 survivors (controls). Results showed that many patients had contacted the primary healthcare system because of infection before they became severely ill, and that the strongest affectable risk factor for death was delay (>24h) between primary healthcare visit and admission to hospital. This shows the need for increased awareness in society and amongst the medical profession of those patients at risk and symptoms that should raise the alarm, leading to more rapid treatment. In Studies I and II we found an increase in both BSIs and mortality, we also saw an increase in antibiotic resistance and multiresistant bacteria, mainly ESBL-producing E. coli. On the other hand, we did not see any coupling between multiresistance and mortality in this Swedish population. E. coli is a gram-negative bacteria that causes most BSIs. Since E. coli is predominantly a urine tract pathogen, Study IV aimed to study BSIs caused by ESBL-producing E. coli originating from the urinary tract. We studied the prevalence of E. coli clones, resistance genes and risk factors, as well as any signs of increased mortality from ESBL-producing E. coli compared to sensitive E. coli. Our main finding was a surprisingly low mortality from ESBL-producing E. coli (3%). Most patients in the ESBL-producing E. coli group received inadequate antibiotic treatment for at least 48h, but we did not see any sign of increased mortality or risk for serious sepsis with circulatory failure in this group. This finding is interesting and opens up for new studies on virulence factors and immunological factors that govern the immune response to BSI. The implementation of cost-effective monitoring systems including clinical microbiological epidemiology and early identification of BSI, together with information campaigns aimed at the public as well as healthcare personnel regarding patients at risk and symptoms giving cause for alarm, should lead to a radical reduction in morbidity and mortality from BSI. This requires new diagnostic tools to individualise both antibiotic treatment and targeted management based on microorganism virulence factors. Modernisation of the medical journal system with algorithms aimed at early identification of risk patients and automated suggestions for empirical antibiotic treatment based on antibiotic resistance seen in previous cultures and local resistance patterns, would certainly improve management. Furthermore, new immunological tests showing the type of immunological reaction to a serious BSI will lead to individualised immunotherapy that, together with antibiotic treatment, will further improve patient care in this important group.
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| 2. |
- Ljungström, Viktor, 1986-
(författare)
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Exploring next-generation sequencing in chronic lymphocytic leukemia
- 2016
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Next-generation sequencing (NGS) techniques have led to major breakthroughs in the characterization of the chronic lymphocytic leukemia (CLL) genome with discovery of recurrent mutations of potential prognostic and/or predictive relevance. However, before NGS can be introduced into clinical practice, the precision of the techniques needs to be studied in better detail. Furthermore, much remains unknown about the genetic mechanisms leading to aggressive disease and resistance to treatment. Hence, in Paper I, the technical performance of a targeted deep sequencing panel including 9 genes was evaluated in 188 CLL patients. We were able to validate 143/155 (92%) selected mutations through Sanger sequencing and 77/82 mutations were concordant in a second targeted sequencing run, indicating that the technique can be introduced in clinical practice. In Paper II we screened 18 NF-κB pathway genes in 315 CLL patients through targeted deep sequencing which revealed a recurrent 4 base-pair deletion in the NFKBIE gene. Screening of NFKBIE in 377 additional cases identified the mutation in ~6% of all CLL patients. We demonstrate that the lesion lead to aberrant NF-κB signaling through impaired interaction with p65 and is associated with unfavorable clinical outcome. In Paper III we sought to delineate the genetic lesions that leads to relapse after fludarabine, cyclophosphamide, and rituximab treatment. Through whole-exome sequencing of pre-treatment and relapse samples from 41 cases we found evidence of frequent selection of subclones harboring driver mutations and subsequent clonal evolution following treatment. We also detected mutations in the ribosomal protein RPS15 in 8 cases (19.5%) and characterization of the mutations through functional assays point to impaired p53 regulation in cells with mutated RPS15. Paper IV aimed at characterizing 70 patients assigned to three major subsets (#1, #2, and #4) through whole-genome sequencing. Besides recurrent exonic driver mutations, we report non-coding regions significantly enriched for mutations in subset #1 and #2 that may facilitate future molecular studies. Collectively, this thesis supports the potential of targeted sequencing for mutational screening of CLL in clinical practice, provides novel insight into the pathobiology of aggressive CLL, and demonstrates the clinical outcome and cellular effects of NFKBIE and RPS15 mutations.
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| 3. |
- Duvetorp, Albert, 1980-
(författare)
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Different Aspects of Psoriasis : Comorbidity, Comedication and Disease Biomarkers
- 2021
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Psoriasis is a common heterogeneous inflammatory disease with its predominant manifestation occurring in the skin. The impact of this disease, however, extends far beyond the skin surface. During the last decades, mounting scientific evidence of psoriasis disease impact on quality of life, stigmatization and comorbidity has led to the predominant view that psoriasis care needs a holistic approach. Epidemiological research is needed to visualize the greater picture whereas research on disease pathomechanisms can provide answers to disease evaluation challenges, facilitate development of new treatments, and provide insights into mechanistical bridges explaining comorbidity occurrence. In study I of this thesis, serum S100A8/A9 was evaluated as a possible biomarker of psoriasis skin disease activity. Dramatic reductions in S100A8 and S100A9 and S100A8/A9 heterocomplex levels were found in lesional psoriasis skin after NB-UVB treatment without any significant reduction occurring in serum. Study II was designed as a retrospective, cross-sectional population study including the adult population of the county of Jönköping. The odds of having pharmacologically treated depression among individuals with psoriasis was compared to the odds of the background population. Psoriasis was associated with an elevated depression risk. Depression was more prevalent among women (both in the background population and among individuals with psoriasis). Young age was associated with higher odds for depression among individuals with psoriasis. Study III was based on the same study population as study II. In this study the comedication burden of individuals with psoriasis was compared to the background population. Comedication assessed were prescription drugs used to treat comorbidity associated with psoriasis in previous scientific publications. Patients with psoriasis were found to have a high comedication burden. Patients receiving systemic treatment for psoriasis had a higher number of different dispensed drugs suggesting that severe disease implies a higher risk of comorbid disease. Study IV was an exploratory study assessing numerous potential biomarkers for psoriasis disease activity. Extensive Luminex analysis of skin and serum samples collected during study I was performed. No serum mediator (potential biomarker of disease activity) showed a significant change after NB-UVB (following correction for multiple testing). In skin, NB-UVB had effects on mediators of the Th17 pathway and multiple chemokines but also previously undescribed or less explored disease mediators. Study II and III suggest that comorbidity and its comedication is common among Swedish psoriasis patients in contact with the health care system. This research reinforces the perception that a holistic approach is needed when treating patients with psoriasis. Behind the failure to identify a biomarker for skin disease activity in study I and IV lurks the questions to how, if or when inflammation in the skin affects systemic inflammation and in extension comorbid disease.
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| 4. |
- Nilsson, R. Anders, 1976-
(författare)
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Dangerous Liaisons : Why Ex-Combatants Return to Violence. Cases from the Republic of Congo and Sierra Leone
- 2008
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- After disarming and demobilizing, why do some ex-combatants re-engage in organized vio-lence, while others do not? Even though former fighters have been identified as a major source of insecurity in post-civil war societies due to their military know-how, there have been few efforts to systematically examine this puzzle. This study fills this research gap by comparing the presence or absence of organized violence in different ex-combatant communi-ties – all the former fighters that used to belong to the same armed faction and who share a common, horizontal identity based on shared war-and peacetime experiences. It does so by analyzing six ex-combatant communities in two countries: ex-Cobra, Cocoye and Ninja in the Republic of Congo and ex-AFRC, CDF and RUF in Sierra Leone. More specifically, three concepts – remarginalization (former fighters’ lack of political influence, personal security or economic assistance), remobilizers (individuals who have the will, capacity and skills to coordinate organized violence in a post-conflict setting) and relationships (whether or not remobilizers share social or material bonds, conducive for war, with ex-combatant communi-ties and each other) – are applied to the six cases, in order to explain why relatively many former CDF, Cobra, Ninja and RUF fighters resorted to violence, while no or hardly any ex-AFRC and Cocoye combatants did the same. Contrary to assumptions found in previous research, this study finds that structural factors, relating to remarginalization, have little ex-planatory value in themselves. Being a rule, rather than an exception, remarginalization can best be understood as a background variable, creating conducive conditions for violence to take place. Instead, the main determinants of ex-combatant violence are whether former fight-ers have access to regional or domestic elites in the market for experienced fighters and to second-tier individuals – such as former mid-level commanders – who can act as intermediar-ies between the two. By utilizing relationships based on selective incentives and social net-works, these two kinds of remobilizers are able to generate the needed enticements and feel-ings of affinity, trust or fear, to convince ex-combatants to resort to arms. These findings demonstrate that the outbreak of ex-combatant violence can only be understood by more clearly incorporating an actor perspective, focusing on three levels of analysis: the elite, mid-level and grass-root.
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| 5. |
- Sjödin, Fredrik, 1978-
(författare)
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Noise in the preschool : health and preventive measures
- 2012
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- This thesis is based on noise recordings and health evaluations carried out at preschools in the northern part of Sweden. Sound level recordings were made on individuals and by use of stationary devices in dining rooms and play halls. Health evaluations were based on ratings by use of questionnaires and by analyses of cortisol.The average equivalent individual noise exposure was 71 dB(A). The average equivalent noise levels in the dining room and playing halls were 64 dB(A). The hearing loss of the employees was significantly higher for the frequencies tested than in an unexposed control group. Symptoms of tinnitus were reported among 31% of the employees. Noise annoyance was rated as somewhat to very annoying, and the voices of the children were the most annoying noise source. The dB(A) level and fluctuations of the noise exposure were significantly correlated with the number of children per department. Stress and energy output were pronounced among the employees. About 30% of the staff experienced strong burnout syndromes. Mental recovery was low as indicated by noise fatigue and high levels of stress after work. Increased cortisol levels during work were associated with higher number of children present at the department.An essential finding of the thesis was that noise and noise sources may impair the pedagogic work, thereby increasing the work load of employees. It is concluded that noise exposure in the preschool, isolated or in combination with other stressors, plays a fundamental role in the building up of acute as well as long term stress. An intervention study implementing six acoustical and seven organizational measures was tested, aimed to improve the noise situation in the departments. Acoustical measures improved the noise situation as well as the rated noise experiences better than the organizational measures.
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| 6. |
- Sundling, Catherine, 1962-
(författare)
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Overall Accessibility of Public Transport for Older Adults
- 2016
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- This thesis is based on four studies that explore accessibility for older adults during whole trips by public transport. The overall goal was to gain knowledge of the interrelationships among key variables and to develop a conceptual model of the overall accessibility of public transport. More specifically, the research goals were: (a) to explore links among the key variables postulated to be involved in overall accessibility and to explore the links between these variables and railway accessibility; (b) to gain a deeper understanding of links between critical incidents in traveling and travel behavior decisions; and (c) to develop a conceptual model of overall accessibility. The key variables contributing to overall accessibility are functional ability (depending partly on the person’s functional limitation or disease), travel behavior, and barriers encountered during whole-trip traveling involving train. Respondents with more than one functional limitation or disease reported lower functional ability than did those with only one such limitation and respondents with low functional ability were less frequent travelers than were those with high functional ability. Frequent travelers reported railway accessibility to be better than did those who traveled less frequently. The main barriers were ticket cost and poor punctuality, but respondents with the lowest functional ability attributed the barriers encountered to their own health. The critical incidents most frequently reported were found in the categories “physical environment onboard vehicles” and “physical environment at stations or stops”, as well as in the “pricing and planning during ticketing” phase of the trip. Five themes of reactions to critical incidents were identified that had resulted in behavior change: firm restrictions, unpredictability, unfair treatment, complicated trips, and earlier adverse experiences. A conceptual model of overall accessibility was developed, grounded in the empirical research results. This model is summarized in the following propositions: Overall accessibility is a reciprocal relationship among the barriers/facilitators encountered, functional ability, and travel behavior. Accessibility emerges in the person–environment interaction. To understand accessibility, past experiences and future expectations should both be considered, because both will guide travel decisions.
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| 7. |
- Szychowska, Malina, 1991-
(författare)
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Effects of visual load on auditory processing
- 2020
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- In daily life, people need to be able to focus on a task while ignoring any task-irrelevant background noise. For example, people who work in an open-space office may have to work on a report while ignoring the background talk among co-workers. Theories of attention argue that processing of task-irrelevant auditory information should become attenuated when attentional capacity is exhausted by task-relevant stimuli, for example a visual task. According to early-filter theory, top-down attenuation of auditory responses is possible at various stages of the auditory pathway through multiple recurrent loops. Furthermore, the adaptive filtering model of selective attention suggests that filtering occurs early when concurrent visual tasks are demanding (e.g., high load) and late when tasks are easy (e.g., low load).The main aim of this thesis was to investigate whether auditory processing is attenuated during concurrent visual load manipulation, and if so, at which stage of the auditory pathway. Recurrent loops that are present throughout the entire auditory pathway should allow top-down modulation of even earliest responses, especially when accompanied by a highly demanding task. Recording these auditory responses during concurrent visual tasks with different levels of load could potentially show at which stages of auditory processing the filtering happens when the task demands are high or low, or there is no task at all.This thesis tested the effects of visual load manipulation on the responses originating from different stages of the auditory pathway: mismatch negativity (MMN) to duration in Study I, MMN to frequency in Study III, auditory steady-state responses (ASSRs) to a 40-Hz modulation frequency in Study IV, and ASSRs to 20-, 40-, and 80-Hz modulation frequencies in Study V. Additionally, Study II compared different control conditions (cascade vs. no-repetition control) for evoking MMN to find a design that reduces confounds in the MMN. Results of Study II showed that cascade and no-repetition control are comparable control conditions for evoking MMN.For the effects of visual load manipulation on auditory MMN (low vs. high load), results showed moderate evidence for the effect of load on duration MMN and moderate evidence for no effect of load on frequency MMN. However, results for the duration MMN might be confounded by physical differences between the low load and high load conditions in the visual task, and by a biased oddball paradigm used to evoke the MMN. Thus, it is most likely that auditory MMN is not affected by visual load (low vs. high).For the effects of visual load on ASSRs (no, low, and high load), results showed moderate to strong evidence for no effects of load manipulation on ASSRs, but some comparisons were inconclusive. The convincing evidence obtained in Studies IV and V points to the robustness of ASSRs against visual load manipulation.Because it is most likely that neither MMN nor ASSRs are affected by visual load manipulation, results presented in this thesis support the idea that attentional resources are modality specific. Because it is possible that filtering occurs at one stage of auditory processing and does not change with the concurrent task demands, the present results do not rule out the early-filter theory. However, results are inconsistent with the adaptive filtering model because filtering of task-irrelevant responses does not vary with the demands of the concurrent task.
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| 8. |
- Zhang, Qi, 1995-
(författare)
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Ion escape from Mars
- 2023
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Licentiatavhandling (övrigt vetenskapligt/konstnärligt)abstract
- When the solar wind reaches the Mars obstacle, mass loading by planetary ions slows down the solar wind and raises the bow shock. The Martian atmosphere is undergoing the a scavenging by the solar wind without the protection of a global magnetic field. Atmospheric escape is an important process for the evolution of the Martian climate. For present Mars, the dominant escape of atmospheric neutrals is through four channels: Jeans escape, photochemical reactions, sputtering and electron impact ionization. Ions above the exobase get accelerated by the solar wind electric field and can escape.We here apply a new method for estimating heavy ion (O+, O+2, and CO+2) escape rates at Mars, which combines a hybrid model and observations. We use observed upstream solar wind parameters as input for a hybrid plasma model, where the total ion upflux at the exobase is a free parameter. We then vary this ion upflux to find the best fit to the observed bow shock location. This method gives us a self-consistent description of the Mars-solar wind interaction, which can be used to study other properties of the solar wind interaction besides escape.
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| 9. |
- Östholm Balkhed, Åse, 1972-
(författare)
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Extended-Spectrum ß-Lactamase-Producing Enterobacteriaceae : Antibiotic consumption, Detection and Resistance Epidemiology
- 2014
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- ESBL-producing Enterobacteriaceae are emerging worldwide and they are frequently multi-drug resistant, thus limiting treatment options for infections caused by these pathogens.The overall aim of the thesis was to investigate ESBL-producing Enterobacteriaceae in a Swedish county.First, we developed a molecular method, a multiplex PCR assay for identification of SHV, TEM and CTX-M genes in clinical isolates of Enterobacteriaceae with an ESBL phenotype.From 2002 until the end of 2007 all isolates of ESBL-producing Enterobacteriaceae in Östergötland, Sweden were further investigated. The prevalence of ESBL-producing Enterobacteriaceae was low, <1%, but increasing,while the antibiotic consumption remained unchanged. CTX-M enzymes, particularly CTX-M group 1, dominate in our region as well as in the rest of Europe.Furthermore, we have investigated antimicrobial susceptibility by performing MIC-testing in a large, well-characterized population of CTX-M-producing E. coli. Only three oral antimicrobial agents (fosfomycin, nitrofurantoin and mecillinam) demonstrated susceptibility above 90%. High susceptibility, >90%, was also demonstrated for carbapenems, colistin, tigecycline and amikacin. Sixty-eight per cent of ESBL-producing E. coli was multi-resistant, and the most common multi-resistance pattern was the ESBL phenotype with decreased susceptibility to trimethoprim, trimethoprim-sulfamethoxazole, ciprofloxacin, gentamicin and tobramycin. Isolates belonging to CTX-M group 9 are generally more susceptible to antibiotics than the CTX-M group 1-producing E. coli. Finally, a prospective multicentre case-control study examined the prevalence of ESBL-producing Enterobacteriaceae in faecal samples before and after travel abroad and the risk factors of acquisition. Sixty-eight of 226 travellers (30%) had ESBL-producing Enterobacteriaceae in the faecal flora. The geographical area visited had the highest impact on acquisition, with highest the risk for travellers visiting the Indian subcontinent, followed by Asia and Africa north of the equator. Also, acquisition of ESBL-producing Enterobacteriaceae during travel is associated with abdominal symptoms such as diarrhoea. Age also seemed to affect the risk of acquiring ESBL-producing Enterobacteriaceae, the highest risks were found among travellers ≥ 65 years.This thesis has contributed to increased understanding of the epidemiology of ESBL-producing Enterobacteriaceae and their susceptibility to both beta-lactam and non-beta-lactam agents.
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| 10. |
- Alvarsson, Jesper J.
(författare)
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Perspectives on wanted and unwanted sounds in outdoor environments : Studies of masking, stress recovery, and speech intelligibility
- 2013
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- An acoustic environment contains sounds from various sound sources, some generally perceived as wanted, others as unwanted. This thesis examines the effects of wanted and unwanted sounds in acoustic environments, with regard to masking, stress recovery, and speech intelligibility.In urban settings, masking of unwanted sounds by sounds from water structures has been suggested as a way to improve the acoustic environment. However, Study I showed that the unwanted (road traffic) sound was better at masking the wanted (water) sound than vice versa, thus indicating that masking of unwanted sounds with sounds from water structures may prove difficult. Also, predictions by a partial loudness model of the auditory periphery overestimated the effect of masking, indicating that centrally located informational masking processes contribute to the effect. Some environments have also been shown to impair stress recovery; however studies using only auditory stimuli is lacking. Study II showed that a wanted (nature) sound improve stress recovery compared to unwanted (road traffic, ambient) sounds. This suggests that the acoustic environment influences stress recovery and that wanted sounds may facilitate stress recovery compared to unwanted sounds. An additional effect of unwanted sounds is impeded speech communication, commonly measured with speech intelligibility models. Study III showed that speech intelligibility starts to be negatively affected when the unwanted (aircraft sound) masker have equal or higher sound pressure level as the speech sound. Three models of speech intelligibility (speech intelligibility index, partial loudness and signal–to–noise ratio) predicted this effect well, with a slight disadvantage for the signal–to–noise ratio model. Together, Study I and III suggests that the partial loudness model is useful for determining effects of wanted and unwanted sounds in outdoor acoustic environments where variations in sound pressure level are large. But, in environments with large variations in other sound characteristics, models containing predictions of central processes would likely produce better results.The thesis concludes that wanted and unwanted characteristics of sounds in acoustic environments affect masking, stress recovery, and speech intelligibility, and that auditory perception models can predict these effects.
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